Max Planck Institute for Biological Cybernetics, Dept. of Physiology of Cognitive Processes, 72076 Tübingen (Germany); Present address: Case NFCR Center for Imaging Research, Dept. of Radiology, Case Western Reserve University, Cleveland, OH (USA).
Chemistry. 2013 Dec 23;19(52):18011-26. doi: 10.1002/chem.201300169. Epub 2013 Nov 7.
Calcium plays a vital role in the human body and especially in the central nervous system. Precise maintenance of Ca(2+) levels is very crucial for normal cell physiology and health. The deregulation of calcium homeostasis can lead to neuronal cell death and brain damage. To study this functional role played by Ca(2+) in the brain noninvasively by using magnetic resonance imaging, we have synthesized a new set of Ca(2+) -sensitive smart contrast agents (CAs). The agents were found to be highly selective to Ca(2+) in the presence of other competitive anions and cations in buffer and in physiological fluids. The structure of CAs comprises Gd(3+)-DO3A (DO3A=1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane) coupled to a Ca(2+) chelator o-amino phenol-N,N,O-triacetate (APTRA). The agents are designed to sense Ca(2+) present in extracellular fluid of the brain where its concentration is relatively high, that is, 1.2-0.8 mM. The determined dissociation constant of the CAs to Ca(2+) falls in the range required to sense and report changes in extracellular Ca(2+) levels followed by an increase in neural activity. In buffer, with the addition of Ca(2+) the increase in relaxivity ranged from 100-157%, the highest ever known for any T1-based Ca(2+)-sensitive smart CA. The CAs were analyzed extensively by the measurement of luminescence lifetime measurement on Tb(3+) analogues, nuclear magnetic relaxation dispersion (NMRD), and (17)O NMR transverse relaxation and shift experiments. The results obtained confirmed that the large relaxivity enhancement observed upon Ca(2+) addition is due to the increase of the hydration state of the complexes together with the slowing down of the molecular rotation and the retention of a significant contribution of the water molecules of the second sphere of hydration.
钙在人体中起着至关重要的作用，特别是在中枢神经系统中。精确维持钙水平对于正常细胞生理和健康非常关键。钙稳态的失调可导致神经元细胞死亡和脑损伤。为了通过磁共振成像非侵入性地研究钙在大脑中发挥的这种功能作用，我们合成了一组新的钙敏聪明对比剂 (CA)。结果发现，在缓冲液和生理液中存在其他竞争阴离子和阳离子的情况下，这些试剂对钙具有高度选择性。CA 的结构包括与钙螯合剂邻氨基苯酚-N,N,O-三乙酸酯 (APTRA) 偶联的 Gd(3+)-DO3A (DO3A=1,4,7-三 (羧甲基)-1,4,7,10-四氮杂环十二烷)。这些试剂旨在感测大脑细胞外液中存在的钙，其浓度相对较高，即 1.2-0.8 mM。CA 与钙的解离常数的测定值落入感测和报告细胞外钙水平变化所需的范围内，随后神经活动增加。在缓冲液中，加入钙后弛豫率增加了 100-157%，这是迄今为止任何基于 T1 的钙敏聪明 CA 中最高的。通过对 Tb(3+)类似物的荧光寿命测量、核磁共振弛豫分散 (NMRD) 和 (17)O NMR 横向弛豫和位移实验，对 CA 进行了广泛分析。结果证实，观察到的钙加合后弛豫率的大幅提高是由于配合物水合状态的增加以及分子旋转速度的减慢以及保留第二水合层水分子的显著贡献所致。
